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1.  Glial–Neuronal Interactions—Implications for Plasticity and Drug Addiction 
The AAPS Journal  2009;11(1):123-132.
Among neuroscientists, astrocytes have for long played Cinderella to their neuron stepsisters. While the importance of glia in regulating brain activity was predicted by Ramon y Cajal more than a century ago (Garcia-Marin et al., Trends. Neurosci. 30:479–787, 2007), these cells, until recently, have been thought to play mainly a passive part in synaptic signaling. Results obtained over the last decade have begun to suggest otherwise. Experiments carried out in a number of labs have shown that glial cells, especially astrocytes, directly participate in synaptic signaling and potentially regulate synaptic plasticity and network excitability. The presence of signaling pathways on astrocytes that are analogous to those at presynaptic terminals suggests a role for these cells in network plasticity. Findings that the same signaling pathways can be activated by receptors for drugs of abuse present on astrocytes suggest a role for these cells in the addictive process. In this review, we summarize current understanding of astrocytic role in synaptic signaling and suggest that a complete understanding of the process of addiction requires a better understanding of the functional role of these cells.
PMCID: PMC2664886  PMID: 19238557
astrocyte; calcium; gliotransmission; nicotinic; synapse; tripartite synapse
2.  A Tale of Two Stories: Astrocyte Regulation of Synaptic Depression and Facilitation 
PLoS Computational Biology  2011;7(12):e1002293.
Short-term presynaptic plasticity designates variations of the amplitude of synaptic information transfer whereby the amount of neurotransmitter released upon presynaptic stimulation changes over seconds as a function of the neuronal firing activity. While a consensus has emerged that the resulting decrease (depression) and/or increase (facilitation) of the synapse strength are crucial to neuronal computations, their modes of expression in vivo remain unclear. Recent experimental studies have reported that glial cells, particularly astrocytes in the hippocampus, are able to modulate short-term plasticity but the mechanism of such a modulation is poorly understood. Here, we investigate the characteristics of short-term plasticity modulation by astrocytes using a biophysically realistic computational model. Mean-field analysis of the model, supported by intensive numerical simulations, unravels that astrocytes may mediate counterintuitive effects. Depending on the expressed presynaptic signaling pathways, astrocytes may globally inhibit or potentiate the synapse: the amount of released neurotransmitter in the presence of the astrocyte is transiently smaller or larger than in its absence. But this global effect usually coexists with the opposite local effect on paired pulses: with release-decreasing astrocytes most paired pulses become facilitated, namely the amount of neurotransmitter released upon spike i+1 is larger than that at spike i, while paired-pulse depression becomes prominent under release-increasing astrocytes. Moreover, we show that the frequency of astrocytic intracellular Ca2+ oscillations controls the effects of the astrocyte on short-term synaptic plasticity. Our model explains several experimental observations yet unsolved, and uncovers astrocytic gliotransmission as a possible transient switch between short-term paired-pulse depression and facilitation. This possibility has deep implications on the processing of neuronal spikes and resulting information transfer at synapses.
Author Summary
Synaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neuronal activity. Because it admittedly underlies learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. Short-term presynaptic plasticity refers to changes occurring over short time scales (milliseconds to seconds) that are mediated by frequency-dependent modifications of the amount of neurotransmitter released by presynaptic stimulation. Recent experiments have reported that glial cells, especially hippocampal astrocytes, can modulate short-term plasticity, but the mechanism of such modulation is poorly understood. Here, we explore a plausible form of modulation of short-term plasticity by astrocytes using a biophysically realistic computational model. Our analysis indicates that astrocytes could simultaneously affect synaptic release in two ways. First, they either decrease or increase the overall synaptic release of neurotransmitter. Second, for stimuli that are delivered as pairs within short intervals, they systematically increase or decrease the synaptic response to the second one. Hence, our model suggests that astrocytes could transiently trigger switches between paired-pulse depression and facilitation. This property explains several challenging experimental observations and has a deep impact on our understanding of synaptic information transfer.
PMCID: PMC3228793  PMID: 22162957
3.  Neuron-glia communication via EphA4/ephrinA3 modulates LTP through glial glutamate transport 
Nature neuroscience  2009;12(10):1285-1292.
Astrocytes are critical participants in synapse development and function, but their role in synaptic plasticity is unclear. Eph receptors and their ephrin ligands have been suggested to regulate neuron-glia interactions and EphA4-mediated ephrin reverse signaling is required for synaptic plasticity in the hippocampus. Here we show that long-term potentiation (LTP) at the CA3-CA1 synapse is modulated by EphA4 in the postsynaptic CA1 cell and by ephrinA3, a ligand of EphA4 that is found in astrocytes. Lack of EphA4 increases the levels of glial glutamate transporters and ephrinA3 modulates transporter currents in astrocytes. Pharmacological inhibition of glial glutamate transporters rescues the LTP defects in EphA4 and ephrinA3 mutant mice. Transgenic overexpression of ephrinA3 in astrocytes reduces glutamate transporter levels and produces focal dendritic swellings possibly caused by glutamate excitotoxicity. These results suggest that EphA4/ephrinA3 signaling is a critical mechanism for astrocytes to regulate synaptic function and plasticity.
PMCID: PMC3922060  PMID: 19734893
4.  Glial cells physiologically modulate clock neurons and circadian behavior in a calcium-dependent manner 
Current biology : CB  2011;21(8):625-634.
An important goal of contemporary neuroscience research is to define the neural circuits and synaptic interactions that mediate behavior. In both mammals and Drosophila, the neuronal circuitry controlling circadian behavior has been the subject of intensive investigation, but roles for glial cells in the networks controlling rhythmic behavior have only begun to be defined in recent studies.
Here, we show that conditional, glial-specific genetic manipulations affecting membrane (vesicle) trafficking, the membrane ionic gradient or calcium signaling lead to circadian arrhythmicity in adult behaving Drosophila. Correlated and reversible effects on a clock neuron peptide transmitter (PDF) and behavior demonstrate the capacity for glia-to-neuron signaling in the circadian circuitry. These studies also reveal the importance of a single type of glial cell – the astrocyte – and glial internal calcium stores in the regulation of circadian rhythms.
This is the first demonstration in any system that adult glial cells can physiologically modulate circadian neuronal circuitry and behavior. A role for astrocytes and glial calcium signaling in the regulation of Drosophila circadian rhythms emphasizes the conservation of cellular and molecular mechanisms that regulate behavior in mammals and insects.
PMCID: PMC3081987  PMID: 21497088
5.  Computational Models of Neuron-Astrocyte Interactions Lead to Improved Efficacy in the Performance of Neural Networks 
The importance of astrocytes, one part of the glial system, for information processing in the brain has recently been demonstrated. Regarding information processing in multilayer connectionist systems, it has been shown that systems which include artificial neurons and astrocytes (Artificial Neuron-Glia Networks) have well-known advantages over identical systems including only artificial neurons. Since the actual impact of astrocytes in neural network function is unknown, we have investigated, using computational models, different astrocyte-neuron interactions for information processing; different neuron-glia algorithms have been implemented for training and validation of multilayer Artificial Neuron-Glia Networks oriented toward classification problem resolution. The results of the tests performed suggest that all the algorithms modelling astrocyte-induced synaptic potentiation improved artificial neural network performance, but their efficacy depended on the complexity of the problem.
PMCID: PMC3357509  PMID: 22649480
6.  Glial cells in neuronal network function 
Numerous evidence demonstrates that astrocytes, a type of glial cell, are integral functional elements of the synapses, responding to neuronal activity and regulating synaptic transmission and plasticity. Consequently, they are actively involved in the processing, transfer and storage of information by the nervous system, which challenges the accepted paradigm that brain function results exclusively from neuronal network activity, and suggests that nervous system function actually arises from the activity of neuron–glia networks. Most of our knowledge of the properties and physiological consequences of the bidirectional communication between astrocytes and neurons resides at cellular and molecular levels. In contrast, much less is known at higher level of complexity, i.e. networks of cells, and the actual impact of astrocytes in the neuronal network function remains largely unexplored. In the present article, we summarize the current evidence that supports the notion that astrocytes are integral components of nervous system networks and we discuss some functional properties of intercellular signalling in neuron–glia networks.
PMCID: PMC2894949  PMID: 20603358
astrocytes; intracellular Ca2+; gliotransmitter release; neuron–glia communication
7.  Cell adhesion molecules in the central nervous system 
Cell Adhesion & Migration  2009;3(1):29-35.
Cell-cell adhesion molecules play key roles at the intercellular junctions of a wide variety of cells, including interneuronal synapses and neuron-glia contacts. Functional studies suggest that adhesion molecules are implicated in many aspects of neural network formation, such as axon-guidance, synapse formation, regulation of synaptic structure and astrocyte-synapse contacts. Some basic cell biological aspects of the assembly of junctional complexes of neurons and glial cells resemble those of epithelial cells. However, the neuron specific junctional machineries are required to exert neuronal functions, such as synaptic transmission and plasticity. In this review, we describe the distribution and function of cell adhesion molecules at synapses and at contacts between synapses and astrocytes.
PMCID: PMC2675146  PMID: 19372758
synapses; cell adhesion molecules; cadherin superfamily; immunoglobulin superfamily; nerve tissue proteins; axons
8.  Artificial Astrocytes Improve Neural Network Performance 
PLoS ONE  2011;6(4):e19109.
Compelling evidence indicates the existence of bidirectional communication between astrocytes and neurons. Astrocytes, a type of glial cells classically considered to be passive supportive cells, have been recently demonstrated to be actively involved in the processing and regulation of synaptic information, suggesting that brain function arises from the activity of neuron-glia networks. However, the actual impact of astrocytes in neural network function is largely unknown and its application in artificial intelligence remains untested. We have investigated the consequences of including artificial astrocytes, which present the biologically defined properties involved in astrocyte-neuron communication, on artificial neural network performance. Using connectionist systems and evolutionary algorithms, we have compared the performance of artificial neural networks (NN) and artificial neuron-glia networks (NGN) to solve classification problems. We show that the degree of success of NGN is superior to NN. Analysis of performances of NN with different number of neurons or different architectures indicate that the effects of NGN cannot be accounted for an increased number of network elements, but rather they are specifically due to astrocytes. Furthermore, the relative efficacy of NGN vs. NN increases as the complexity of the network increases. These results indicate that artificial astrocytes improve neural network performance, and established the concept of Artificial Neuron-Glia Networks, which represents a novel concept in Artificial Intelligence with implications in computational science as well as in the understanding of brain function.
PMCID: PMC3079756  PMID: 21526157
9.  Contribution of Glial-Neuronal Interactions to the Neuroendocrine Control of Female Puberty 
The European journal of neuroscience  2010;32(12):2003-2010.
Mammalian puberty is initiated by an increasedpulsatile release of the neuropeptide gonadotropin-releasing hormone (GnRH) from hypothalamic neuroendocrine neurons. Although this increase is primarily set in motion by neuronal networks synaptically connected to GnRH neurons, glial cells contribute to the process via at least two mechanisms. One involves production of growth factors acting via receptors endowed with either serine-threonine kinase or tyrosine kinase activity. The other involves plastic rearrangements of glia-GnRH neuron adhesiveness. Growth factors of the epidermal growth factor (EGF) family acting via erbB receptors play a major in glia-to GnRH neuron communication. In turn, neurons facilitate astrocytic erbB signaling via glutamate-dependent cleavage of erbB ligand precursors. Genetic disruption of erbB receptors delays female sexual development due to impaired erbB ligand-induced glial prostaglandin E2 (PGE2) release. The adhesiveness of glial cells to GnRH neurons involves at least two different cell-cell communication systems endowed with both adhesive and intracellular signaling capabilities. One is provided by Synaptic Cell Adhesion Molecule (SynCAM1), which establishes astrocyte-GnRH neuron adhesiveness via homophile interactions; the other involves the heterophilic interaction of neuronal contactin with glial Receptor-like Protein Tyrosine Phosphatase-β (RPTPβ). These finding indicate that the interaction of glial cells with GnRH neurons involves not only secreted bioactive molecules, but also cell-surface adhesive proteins able to set in motion intracellular signaling cascades.
PMCID: PMC3058235  PMID: 21143655
glial cells; hypothalamus; neuroendocrine neurons; female sexual development; glial-neuronal interactions; intercellular signaling
10.  Bidirectional Coupling between Astrocytes and Neurons Mediates Learning and Dynamic Coordination in the Brain: A Multiple Modeling Approach 
PLoS ONE  2011;6(12):e29445.
In recent years research suggests that astrocyte networks, in addition to nutrient and waste processing functions, regulate both structural and synaptic plasticity. To understand the biological mechanisms that underpin such plasticity requires the development of cell level models that capture the mutual interaction between astrocytes and neurons. This paper presents a detailed model of bidirectional signaling between astrocytes and neurons (the astrocyte-neuron model or AN model) which yields new insights into the computational role of astrocyte-neuronal coupling. From a set of modeling studies we demonstrate two significant findings. Firstly, that spatial signaling via astrocytes can relay a “learning signal” to remote synaptic sites. Results show that slow inward currents cause synchronized postsynaptic activity in remote neurons and subsequently allow Spike-Timing-Dependent Plasticity based learning to occur at the associated synapses. Secondly, that bidirectional communication between neurons and astrocytes underpins dynamic coordination between neuron clusters. Although our composite AN model is presently applied to simplified neural structures and limited to coordination between localized neurons, the principle (which embodies structural, functional and dynamic complexity), and the modeling strategy may be extended to coordination among remote neuron clusters.
PMCID: PMC3248449  PMID: 22242121
11.  Neuron-Glia Interaction as a Possible Glue to Translate the Mind-Brain Gap: A Novel Multi-Dimensional Approach Toward Psychology and Psychiatry 
Neurons and synapses have long been the dominant focus of neuroscience, thus the pathophysiology of psychiatric disorders has come to be understood within the neuronal doctrine. However, the majority of cells in the brain are not neurons but glial cells including astrocytes, oligodendrocytes, and microglia. Traditionally, neuroscientists regarded glial functions as simply providing physical support and maintenance for neurons. Thus, in this limited role glia had been long ignored. Recently, glial functions have been gradually investigated, and increasing evidence has suggested that glial cells perform important roles in various brain functions. Digging up the glial functions and further understanding of these crucial cells, and the interaction between neurons and glia may shed new light on clarifying many unknown aspects including the mind-brain gap, and conscious-unconscious relationships. We briefly review the current situation of glial research in the field, and propose a novel translational research with a multi-dimensional model, combining various experimental approaches such as animal studies, in vitro & in vivo neuron-glia studies, a variety of human brain imaging investigations, and psychometric assessments.
PMCID: PMC3804762  PMID: 24155727
translational research; neuron-glia interaction; mind-brain gap; unconscious; neuropsychoanalysis
12.  The computational power of astrocyte mediated synaptic plasticity 
Research in the last two decades has made clear that astrocytes play a crucial role in the brain beyond their functions in energy metabolism and homeostasis. Many studies have shown that astrocytes can dynamically modulate neuronal excitability and synaptic plasticity, and might participate in higher brain functions like learning and memory. With the plethora of astrocyte mediated signaling processes described in the literature today, the current challenge is to identify, which of these processes happen under what physiological condition, and how this shapes information processing and, ultimately, behavior. To answer these questions will require a combination of advanced physiological, genetical, and behavioral experiments. Additionally, mathematical modeling will prove crucial for testing predictions on the possible functions of astrocytes in neuronal networks, and to generate novel ideas as to how astrocytes can contribute to the complexity of the brain. Here, we aim to provide an outline of how astrocytes can interact with neurons. We do this by reviewing recent experimental literature on astrocyte-neuron interactions, discussing the dynamic effects of astrocytes on neuronal excitability and short- and long-term synaptic plasticity. Finally, we will outline the potential computational functions that astrocyte-neuron interactions can serve in the brain. We will discuss how astrocytes could govern metaplasticity in the brain, how they might organize the clustering of synaptic inputs, and how they could function as memory elements for neuronal activity. We conclude that astrocytes can enhance the computational power of neuronal networks in previously unexpected ways.
PMCID: PMC3485583  PMID: 23125832
astrocytes; synaptic plasticity; spike-timing-dependent plasticity; STDP; metaplasticity; heterosynaptic plasticity; computation; calcium
13.  Transgenic mice expressing a cameleon fluorescent Ca2+ indicator in astrocytes and Schwann cells allow study of glial cell Ca2+ signals in situ and in vivo 
Journal of neuroscience methods  2009;181(2):212-226.
Glial cell Ca2+ signals play a key role in glial-neuronal and glial-glial network communication. Numerous studies have thus far utilized cell-permeant and injected Ca2+ indicator dyes to investigate glial Ca2+ signals in vitro and in situ. Genetically encoded fluorescent Ca2+ indicators have emerged as novel probes for investigating cellular Ca2+ signals. We have expressed one such indicator protein, the YC 3.60 cameleon, under the control of the S100β promoter and directed its expression predominantly in astrocytes and Schwann cells. Expression of YC 3.60 extended into the entire cellular cytoplasmic compartment and the fine terminal processes of protoplasmic astrocytes and Schwann cell Cajal bands. In the brain, all the cells known to express S100β in the adult or during development, expressed YC 3.60. While expression was most extensive in astrocytes, other glial cell types that express S100β, such as NG2 and CNP-positive oligodendrocyte progenitor cells (OP cells), microglia, and some of the large motor neurons in the brain stem, also contained YC 3.60 fluorescence. Using a variety of known in situ and in vivo assays, we found that stimuli known to elicit Ca2+ signals in astrocytes caused substantial and rapid Ca2+ signals in the YC 3.60-expressing astrocytes. In addition, forepaw stimulation while imaging astrocytes through a cranial window in the somatosensory cortex in live mice, revealed robust evoked and spontaneous Ca2+ signals. These results, for the first time, show that genetically encoded reporter is capable of recording activity-dependent Ca2+ signals in the astrocyte processes, and networks.
PMCID: PMC3142666  PMID: 19454294
YC 3.60 cameleon; Astrocytes; Schwann cells; Transgenic mice
14.  Tripartite synapses: roles for astrocytic purines in the control of synaptic physiology and behavior 
Neuropharmacology  2009;57(4):343-346.
Astrocytes are known to release several transmitters to impact neuronal activity. Cell-specific molecular genetic attenuation of vesicular release has shown that ATP is a primary astrocytic transmitter in situ and in vivo. In this review, we discuss the biology of astrocytic ATP release highlighting the exciting discovery that lysosomes might be primary stores for the release of this gliotransmitter. In addition, we discuss the role of ATP and its metabolite adenosine on synaptic transmission and the coordination of synaptic networks. Finally, we discuss the recent elucidation of the involvement of this form of glial signaling in the modulation of mammalian behavior. By controlling neuronal A1-receptor signaling, astrocytes modulate mammalian sleep homeostasis and are essential for mediating the cognitive consequences of sleep deprivation. These discoveries begin to paint a new picture of brain function in which slow signaling glia modulate fast synaptic transmission and neuronal firing to impact behavioral output. Because these cells have privileged access to synapses, they may be valuable targets for the development of novel therapies for many neurological and psychiatric conditions.
PMCID: PMC3190118  PMID: 19577581
15.  The Role of Glial Cells in Drug Abuse 
Current drug abuse reviews  2009;2(1):76-82.
Neuronal dysfunction in the prefrontal cortex, limbic structures, nucleus accumbens and ventral tegmental area is considered to underlie the general physiopathological mechanisms for substance use disorders. Glutamatergic, dopaminergic and opioidoergic neuronal mechanisms in those brain areas have been targeted in the development of pharmacotherapies for drug abuse and dependence. However, despite the pivotal role of neurons in the mechanisms of addiction, these cells are not the only cell type in charge of sustaining and regulating neurotransmission. Glial cells, particularly astrocytes, play essential roles in the regulation of glutamatergic neurotransmission, neurotransmitter metabolism, and supply of energy substrates for synaptic transmission. In addition, astrocytes are markedly affected by exposure to ethanol and other substances of abuse. These features of astrocytes suggest that alterations in the function of astrocytes and other glial cells in reward circuits may contribute to drug addiction. Recent research has shown that the control of glutamate uptake and the release of neurotrophic factors by astrocytes influences behaviors of addiction and may play modulatory roles in psychostimulant, opiate, and alcohol abuse. Less is known about the contributions of microglia and oligodendrocytes to drug abuse, although, given the ability of these cells to produce growth factors and cytokines in response to alterations in synaptic transmission, further research should better define their role in drug addiction. The available knowledge on the involvement of glial cells in addictive behaviors suggests that regulation of glutamate transport and neurotrophins may constitute new avenues for the treatment of drug addiction.
PMCID: PMC2709875  PMID: 19606280
Addiction; glia; astrocytes; oligodendrocytes; microglia; alcoholism; opiates; psychostimulants
16.  Alteration of astrocytes and Wnt/β-catenin signaling in the frontal cortex of autistic subjects 
Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. To date the etiology of this disorder is poorly understood. Studies suggest that astrocytes play critical roles in neural plasticity by detecting neuronal activity and modulating neuronal networks. Recently, a number of studies suggested that an abnormal function of glia/astrocytes may be involved in the development of autism. However, there is yet no direct evidence showing how astrocytes develop in the brain of autistic individuals.
Study subjects include brain tissue from autistic subjects, BTBR T + tfJ (BTBR) and Neuroligin (NL)-3 knock-down mice. Western blot analysis, Immunohistochemistry and confocal microscopy studies have been used to examine the density and morphology of astrocytes, as well as Wnt and β-catenin protein expression.
In this study, we demonstrate that the astrocytes in autisitc subjects exhibit significantly reduced branching processes, total branching length and cell body sizes. We also detected an astrocytosis in the frontal cortex of autistic subjects. In addition, we found that the astrocytes in the brain of an NL3 knockdown mouse exhibited similar alterations to what we found in the autistic brain. Furthermore, we detected that both Wnt and β-catenin proteins are decreased in the frontal cortex of autistic subjects. Wnt/β-catenin pathway has been suggested to be involved in the regulation of astrocyte development.
Our findings imply that defects in astrocytes could impair neuronal plasticity and partially contribute to the development of autistic-like behaviors in both humans and mice. The alteration of Wnt/β-catenin pathway in the brain of autistic subjects may contribute to the changes of astrocytes.
PMCID: PMC3544729  PMID: 22999633
Autism; Astrocytes; Morphology; Wnt/β-catenin pathway; Neural plasticity
17.  Adenosine and Glutamate Signaling in Neuron-Glial interactions: Implications in Alcoholism and Sleep Disorders 
Recent studies have demonstrated that the function of glia is not restricted to the support of neuronal function. Especially, astrocytes are essential for neuronal activity in the brain. Astrocytes actively participate in synapse formation and brain information processing by releasing or uptaking gliotransmitters such as glutamate, D-serine, adenosine 5′-triphosphate (ATP) and adenosine. In the central nervous system, adenosine plays an important role in regulating neuronal activity as well as in controlling other neurotransmitter systems such as GABA, glutamate and dopamine. Ethanol increases extracellular adenosine levels, which regulates the ataxic and hypnotic/sedative (somnogenic) effects of ethanol. Adenosine signaling is also involved in the homeostasis of major inhibitory-excitatory neurotransmission (i.e. GABA or glutamate) through neuron-glial interactions, which regulates the effect of ethanol and sleep. Adenosine transporters or astrocytic SNARE-mediated transmitter release regulates extracellular or synaptic adenosine levels. Adenosine then exerts its function through several adenosine receptors and regulates glutamate levels in the brain. This review presents novel findings on how neuron-glial interactions, particularly adenosinergic signaling and glutamate uptake activity involving glutamate transporter 1 (GLT1), are implicated in alcoholism and sleep disorders.
PMCID: PMC3349794  PMID: 22309182
Adenosine; Glutamate; Alcoholism; Sleep; Signaling; Pharmacology
18.  How do astrocytes shape synaptic transmission? Insights from electrophysiology 
A major breakthrough in neuroscience has been the realization in the last decades that the dogmatic view of astroglial cells as being merely fostering and buffering elements of the nervous system is simplistic. A wealth of investigations now shows that astrocytes actually participate in the control of synaptic transmission in an active manner. This was first hinted by the intimate contacts glial processes make with neurons, particularly at the synaptic level, and evidenced using electrophysiological and calcium imaging techniques. Calcium imaging has provided critical evidence demonstrating that astrocytic regulation of synaptic efficacy is not a passive phenomenon. However, given that cellular activation is not only represented by calcium signaling, it is also crucial to assess concomitant mechanisms. We and others have used electrophysiological techniques to simultaneously record neuronal and astrocytic activity, thus enabling the study of multiple ionic currents and in depth investigation of neuro-glial dialogues. In the current review, we focus on the input such approach has provided in the understanding of astrocyte-neuron interactions underlying control of synaptic efficacy.
PMCID: PMC3787198  PMID: 24101894
glia; neurons; neuroglial interactions; synapses; ionic channels; plasticity; dual recordings; electrophysiology
19.  Glial cells in (patho)physiology 
Journal of Neurochemistry  2012;121(1):4-27.
Neuroglial cells define brain homeostasis and mount defense against pathological insults. Astroglia regulate neurogenesis and development of brain circuits. In the adult brain, astrocytes enter into intimate dynamic relationship with neurons, especially at synaptic sites where they functionally form the tripartite synapse. At these sites astrocytes regulate ion and neurotransmitter homeostasis, metabolically support neurons and monitor synaptic activity; one of the readouts of the latter manifests in astrocytic intracellular Ca2+ signals. This form of astrocytic excitability can lead to release of chemical transmitters via Ca2+-dependent exocytosis. Once in the extracellular space, gliotransmitters can modulate synaptic plasticity and cause changes in behavior. Besides these physiological tasks, astrocytes are fundamental for progression and outcome of neurological diseases. In Alzheimer’s disease, for example, astrocytes may contribute to the etiology of this disorder. Highly lethal glial-derived tumors use signaling trickery to coerce normal brain cells to assist tumor invasiveness. This review sheds new light on the brain operation in health and disease, but also points to many unknowns.
PMCID: PMC3304021  PMID: 22251135
astrocytes; disease; health; metabolism; neurogenesis; signaling
20.  EphrinBs regulate D-serine synthesis and release in astrocytes 
There is growing evidence that astrocytes play critical roles in neuron-glial interactions at the synapse. Astrocytes are believed to regulate pre- and post-synaptic structures and functions, in part, by the release of gliotransmitters such as glutamate, ATP and D-serine; however, little is known of how neurons and astrocytes communicate to regulate these processes. Here, we investigated a family of transmembrane proteins called ephrins and Eph receptors that are expressed in the synapse and are known to regulate synaptic transmission and plasticity. In addition to their presence on CA1 hippocampal neurons, we determined that ephrins and Eph receptors are also expressed on hippocampal astrocytes. Stimulation of hippocampal astrocytes with soluble ephrinB3, known to be expressed on CA1 post-synaptic dendrites, enhanced D-serine synthesis and release in culture. Conversely, ephrinB3 had no effect on D-serine release from astrocytes deficient in EphB3 and EphA4, which are the primary receptors for ephrinB3. Eph receptors mediate this response through interactions with PICK1 and by dephosphorylating PKCα to activate the conversion of L-serine to D-serine by serine racemase. These findings are supported in vivo, where reduced D-serine levels and synaptic transmissions are observed in the absence of EphB3 and EphA4. These data support a role for ephrins and Eph receptors in regulating astrocyte gliotransmitters, which may have important implications on synaptic transmission and plasticity.
PMCID: PMC3073557  PMID: 21106840
Ephrins; Eph receptors; Astrocyte; glutamate; D-serine; gliotransmitter
21.  Astrocyte-Synapse Structural Plasticity 
Neural Plasticity  2014;2014:232105.
The function and efficacy of synaptic transmission are determined not only by the composition and activity of pre- and postsynaptic components but also by the environment in which a synapse is embedded. Glial cells constitute an important part of this environment and participate in several aspects of synaptic functions. Among the glial cell family, the roles played by astrocytes at the synaptic level are particularly important, ranging from the trophic support to the fine-tuning of transmission. Astrocytic structures are frequently observed in close association with glutamatergic synapses, providing a morphological entity for bidirectional interactions with synapses. Experimental evidence indicates that astrocytes sense neuronal activity by elevating their intracellular calcium in response to neurotransmitters and may communicate with neurons. The precise role of astrocytes in regulating synaptic properties, function, and plasticity remains however a subject of intense debate and many aspects of their interactions with neurons remain to be investigated. A particularly intriguing aspect is their ability to rapidly restructure their processes and modify their coverage of the synaptic elements. The present review summarizes some of these findings with a particular focus on the mechanisms driving this form of structural plasticity and its possible impact on synaptic structure and function.
PMCID: PMC3910461  PMID: 24511394
22.  In vivo astrocytic Ca2+ signaling in health and brain disorders 
Future neurology  2013;8(5):DOI 10.2217/fnl.13.38.
Astrocytes are the predominant glial cell type in the CNS. Although astrocytes are electrically nonexcitable, their excitability is manifested by their Ca2+ signaling, which serves as a mediator of neuron–glia bidirectional interactions via tripartite synapses. Studies from in vivo two-photon imaging indicate that in healthy animals, the properties of spontaneous astrocytic Ca2+ signaling are affected by animal species, age, wakefulness and the location of astrocytes in the brain. Intercellular Ca2+ waves in astrocytes can be evoked by a variety of stimulations. In animal models of some brain disorders, astrocytes can exhibit enhanced Ca2+ excitability featured as regenerative intercellular Ca2+ waves. This review first briefly summarizes the astrocytic Ca2+ signaling pathway and the procedure of in vivo two-photon Ca2+ imaging of astrocytes. It subsequently summarizes in vivo astrocytic Ca2+ signaling in health and brain disorders from experimental studies of animal models, and discusses the possible mechanisms and therapeutic implications underlying the enhanced Ca2+ excitability in astrocytes in brain disorders. Finally, this review summarizes molecular genetic approaches used to selectively manipulate astrocyte function in vivo and their applications to study the role of astrocytes in synaptic plasticity and brain disorders.
PMCID: PMC3873150  PMID: 24376372
Alzheimer's disease; G-protein coupled receptors; in vivo imaging; intercellular Ca2+ waves; IP3 receptor; molecular genetics; photothrombosis; spontaneous Ca2+ signaling; status epilepticus; traumatic brain injury; two-photon microscopy
23.  L-DOPA Uptake in Astrocytic Endfeet Enwrapping Blood Vessels in Rat Brain 
Parkinson's Disease  2012;2012:321406.
Astrocyte endfeet surround brain blood vessels and can play a role in the delivery of therapeutic drugs for Parkinson's disease. However, there is no previous evidence of the presence of LAT transporter for L-DOPA in brain astrocytes except in culture. Using systemic L-DOPA administration and a combination of patch clamp, histochemistry and confocal microscopy we found that L-DOPA is accumulated mainly in astrocyte cell bodies, astrocytic endfeet surrounding blood vessels, and pericytes. In brain slices: (1) astrocytes were exposed to ASP+, a fluorescent monoamine analog of MPP+; (2) ASP+ taken up by astrocytes was colocalized with L-DOPA fluorescence in (3) glial somata and in the endfeet attached to blood vessels; (4) these astrocytes have an electrogenic transporter current elicited by ASP+, but intriguingly not by L-DOPA, suggesting a different pathway for monoamines and L-DOPA via astrocytic membrane. (5) The pattern of monoamine oxidase (MAO type B) allocation in pericytes and astrocytic endfeet was similar to that of L-DOPA accumulation. We conclude that astrocytes control L-DOPA uptake and metabolism and, therefore, may play a key role in regulating brain dopamine level during dopamine-associated diseases. These data also suggest that different transporter mechanisms may exist for monoamines and L-DOPA.
PMCID: PMC3409556  PMID: 22888467
24.  Long-Term Culture of Astrocytes Attenuates the Readily Releasable Pool of Synaptic Vesicles 
PLoS ONE  2012;7(10):e48034.
The astrocyte is a major glial cell type of the brain, and plays key roles in the formation, maturation, stabilization and elimination of synapses. Thus, changes in astrocyte condition and age can influence information processing at synapses. However, whether and how aging astrocytes affect synaptic function and maturation have not yet been thoroughly investigated. Here, we show the effects of prolonged culture on the ability of astrocytes to induce synapse formation and to modify synaptic transmission, using cultured autaptic neurons. By 9 weeks in culture, astrocytes derived from the mouse cerebral cortex demonstrated increases in β-galactosidase activity and glial fibrillary acidic protein (GFAP) expression, both of which are characteristic of aging and glial activation in vitro. Autaptic hippocampal neurons plated on these aging astrocytes showed a smaller amount of evoked release of the excitatory neurotransmitter glutamate, and a lower frequency of miniature release of glutamate, both of which were attributable to a reduction in the pool of readily releasable synaptic vesicles. Other features of synaptogenesis and synaptic transmission were retained, for example the ability to induce structural synapses, the presynaptic release probability, the fraction of functional presynaptic nerve terminals, and the ability to recruit functional AMPA and NMDA glutamate receptors to synapses. Thus the presence of aging astrocytes affects the efficiency of synaptic transmission. Given that the pool of readily releasable vesicles is also small at immature synapses, our results are consistent with astrocytic aging leading to retarded synapse maturation.
PMCID: PMC3482238  PMID: 23110166
25.  Emerging role of glial cells in the control of body weight 
Molecular Metabolism  2012;1(1-2):37-46.
Glia are the most abundant cell type in the brain and are indispensible for the normal execution of neuronal actions. They protect neurons from noxious insults and modulate synaptic transmission through affectation of synaptic inputs, release of glial transmitters and uptake of neurotransmitters from the synaptic cleft. They also transport nutrients and other circulating factors into the brain thus controlling the energy sources and signals reaching neurons. Moreover, glia express receptors for metabolic hormones, such as leptin and insulin, and can be activated in response to increased weight gain and dietary challenges. However, chronic glial activation can be detrimental to neurons, with hypothalamic astrocyte activation or gliosis suggested to be involved in the perpetuation of obesity and the onset of secondary complications. It is now accepted that glia may be a very important participant in metabolic control and a possible therapeutical target. Here we briefly review this rapidly advancing field.
PMCID: PMC3757650  PMID: 24024117
Astrocytes; Gliosis; Metabolic control; Hypothalamus; Obesity

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